Control of the transition between the different phases of the cell cycle during mitosis or meiosis is ensured by a set of proteins the enzymatic activities of which are associated with different states of phosphorylation. These states are controlled by two major classes of enzymes: the kinases and the phosphatases.
The synchronization of the different phases of the cell cycle thus allows the reorganization of the cell architecture at each cycle throughout the living world (microorganisms, yeast, vertebrates, plants). Among the kinases, the cycline-dependent kinases (CDKs) play a major role in this control of the cell cycle. The enzymatic activity of these different CDKs is controlled by two other families of enzymes which work in opposition (Jessus and Ozon, Prog. Cell Cycle Res. (1995), 1, 215-228). The first includes kinases such as Wee1 and Mik1 which deactivate the CDKs by phosphorylating certain amino acids (Den Haese et al., Mol. Biol. Cell (1995), 6, 371-385). The second includes phosphatases such as Cdc25 which activate the CDKs by dephosphorylating the tyrosine and threonine residues of CDKs (Gould et al., Science (1990), 250, 1573-1576).
The phosphatases are classified in 3 groups: the serine/threonine phosphatases (PPases), the tyrosine phosphatases (PTPases) and the dual-specificity phosphatases (DSPases). These phosphatases play an important role in the regulation of numerous cell functions.
As regards human cdc25 phosphatases, 3 genes (cdc25-A, cdc25-B and cdc25-C) code for the cdc25proteins. Moreover, variants originating from the alternative splicing of the gene cdc25B have been identified: these are cdc25B1, cdc25B2 and cdc25B3 (Baldin et al., Oncogene (1997), 14, 2485-2495).
The role of the Cdc25 phosphatases in oncogenesis is now better known and the action mechanisms of these phosphatases are illustrated in particular in the following references: Galaktionov et al., Science (1995), 269, 1575-1577; Galaktionov et al., Nature (1996), 382, 511-517; and Mailand et al., Science (2000), 288, 1425-1429.
In particular, the overexpression of the different forms of cdc25 is now reported in numerous series of human tumors:                Breast cancer: cf. Cangi et al., Résumé 2984, AACR meeting San Francisco, 2000);        Lymphomas: cf. Hernandez et al., Int. J. Cancer (2000), 89, 148-152 and Hernandez et al., Cancer Res. (1998), 58, 1762-1767;        Cancers of the neck and the head: cf. Gasparotto et al., Cancer Res. (1997), 57, 2366-2368.        
Moreover, E. Sausville's group reports an inverse correlation between the level of expression of cdc25-B in a panel of 60 lines and their sensitivities to CDK inhibitors, suggesting that the presence of cdc25 can provide resistance to certain antineoplastic agents and more particularly to CDK inhibitors (Hose et al., Proceedings of AACR, Abstract 3571, San Francisco, 2000).
Among other targets, the pharmaceutical industry is therefore currently researching compounds capable of inhibiting the Cdc25 phosphatases in order to use them in particular as anti-cancer agents.
The Cdc25 phosphatases also play a role in the neurodegenerative diseases such as Alzheimer's disease (cf. Zhou et al., Cell Mol. Life Sci. (1999), 56(9-10), 788-806; Ding et al., Am. J. Pathol. (2000), 157(6), 1983-90; Vincent et al., Neuroscience (2001), 105(3), 639-50) so that it is also possible to envisage using compounds possessing an inhibition activity on these phosphatases for treating these diseases.
Another problem addressed by the invention is research into medicaments intended to prevent or treat the rejection of organ transplants or also to treat auto-immune diseases. In these disorders/diseases, the non-appropriate activation of the lymphocytes and the monocytes/macrophages is involved. Immunosuppressive medicaments known at present have side-effects which could be reduced or modified by products specifically targeting the signalling routes in the haematopoietic cells which initiate and maintain inflammation.
Firstly, a subject of the invention is novel inhibitors of cdc25 phosphatases (in particular of cdc25-C phosphatase), which are 4,7-dioxobenzothiazole-2-carboxamide derivatives and correspond to the general formula (I) defined hereafter. Given the above, these compounds are capable of being used as medicaments, in particular in the treatment and/or the prevention of the following diseases or disorders:
inhibition of tumor proliferation alone or in combination with other treatments;
inhibition of normal cell proliferation alone or in combination with other treatments;                neurodegenerative diseases such as Alzheimer's disease;        prevention of spontaneous alopecia;        prevention of alopecia induced by exogenous products;        prevention of radiation-induced alopecia;        prevention of the spontaneous or induced apoptosis of normal cells;        prevention of meiosis and/or fertilization;        prevention of the maturation of the oocytes;        all the diseases/all the disorders corresponding to uses reported for CDK inhibitors, and in particular non-tumorous proliferative diseases (for example: angiogenesis, psoriasis or restenosis), tumorous proliferative diseases, parasitology (proliferation of protozoans), viral infections, neurodegenerative diseases, myopathies; and/or        all diseases/all disorders corresponding to clinical uses of vitamin K and its derivatives.        
Moreover, the compounds of the present invention are also, because of their inhibition properties on the cdc25 phosphatases, capable of being used for inhibiting or preventing the proliferation of microorganisms, in particular yeasts. One of the advantages of these compounds is their low toxicity on healthy cells.